RVG-functionalized microglial membrane-coated cerium-gallic acid metal-organic frameworks for multi-target Alzheimer's therapy.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by aberrant β-amyloid (Aβ) aggregation, oxidative stress, neuroinflammation, and disrupted metal ion homeostasis, which limit the efficacy of conventional single-target therapies. To address these intertwined pathological processes, we developed a multifunctional nanotherapeutic platform based on a cerium-gallic acid bio-metal-organic framework (CeGA-MOF). Reversible Ce3+/Ce4+ redox cycling enables efficient reactive oxygen species (ROS) scavenging, while gallic acid serves as both an organic ligand and metal chelator, inhibiting metal ion-mediated Aβ aggregation and alleviating oxidative stress-associated neurotoxicity, along with its intrinsic anti-inflammatory activity. To enhance in vivo stability and brain delivery, CeGA-MOF was coated with microglial membranes and functionalized with rabies virus glycoprotein (RVG) peptide, yielding a biomimetic nanosystem, CeGA-MOF/B/R. The microglial membrane provides immune evasion and inflammation-guided targeting, while RVG facilitates blood-brain barrier penetration. In vitro, CeGA-MOF/B/R effectively chelates Cu2+, Zn2+, and Fe3+, suppresses metal ion-induced Aβ aggregation, and protects neurons. In APP/PS1 transgenic mice, it reduced cerebral Aβ, promoted anti-inflammatory microglial polarization, and improved learning and memory, highlighting its potential as a biomimetic nanoplatform for synergistic AD therapy.